Apolipoprotein E (apoE) is a liver-derived plasma protein. This protein is also made by macrophages. Apolipoprotein E (apoE) is an anti-atherogenic protein which inhibits the development of atherosclerotic lesions in humans and in animal models of atherosclerosis. ApoE has immunomodulatory properties and other direct effects on cells in vitro. Liver-directed gene transfer of apoE causes reduction of foam cells and increased vascular smooth muscle cell composition of atherosclerotic lesions in mice. However, the cellular mechanism(s) by which apoE inhibits initial lesion activation are not known. The central hypothesis is: apoE inhibits atherosclerosis by modulating the local inflammatory response within the vessel wall. The Specific Aims of this project proposal are: 1) To determine the mechanisms in vivo by which apoE results in loss of foam cell mass and promotes smooth muscle cell and matrix content within atherosclerotic lesions. The direct effects of apoE being synergistic with cholesterol reduction will be tested. The kinetics of the loss in foam cells induced by apoE will be determined. The ability of apoE to inhibit atherogenesis will be compared to that of apoE3. 2) To utilize an in vitro model of inflammation to define the mechanisms by which apoE reduces foam cells and promotes a fibrotic response. An in vitro model of macrophage activation by low molecular weight hyaluronic acid will be used to test the direct and indirect effects of apoE on macrophage and T cell inflammatory function. The hypothesis that apoE regulates macrophage lipid loading and vascular smooth muscle cell function directly or through T cells will be tested. 3) To test the hypothesis that the anti-atherogenic effect of apoE is in part mediated through its effects on T cells in vivo. T cells or specific subsets may play a role in early atherogenesis. The kinetics of early atherosclerotic lesion formation in apoE deficient mice that are deficient in lymphocytes will be investigated. ApoE deficient mice that are deficient in either MHC class I or MHC class II have been generated and will be studied to determine the effect of selective deficiency or CD4 or CD8 cells. Finally, the ability of apoE to inhibit atherosclerosis in the absence of T cells will be tested. These studies will provide greater understanding of the role of the local inflammatory response in atherosclerosis and its regulation by apoE.